Cardiac and vascular disease, most prominent among them atherosclerosis, have emerged as the number one killer of modern man. In the search for the central causative factor for this scourge of modern man, cholesterol quickly rose to prominence.
From the very outset of atherosclerosis research, it has simply been assumed that endovascular (i.e.: blood component) factors are responsible for the genesis of both micro and macrovascular disease. In other words, intrinsic characteristics of the vascular endothelium and wall were assumed to be secondary in the genesis of vascular pathology of all causes, whether atherosclerotic, inflammatory or other. The one credible challenge to this assumption would appear to be nitrates' ability to ameliorate the effects of atherosclerosis (nitrates act predominantly in the vessel wall and, through release of Nitric Oxide, cause dilation of arteries and arterioles). However, while there is anecdotal and clinical evidence that nitrate-related vasodilation does indeed attenuate the severity of symptoms related to atherosclerosis, there is no evidence to suggest that nitrates have any effect on the genesis or progression of the atherosclerotic lesions themselves (experiments conducted on diabetics showed impaired arterial dilation at early stages of the disease, but no causal connection of this phenomenon to atherosclerosis has ever been proven).
As shall be demonstrated through the course of the discussion that follows, the absence of any clinical or laboratory evidence regarding innate pathology of the vascular wall, as well as the absence of any effective therapies targeted at the vascular wall itself thus supports the thesis that diseases of the vascular wall are primarily a result of insults that are extrinsic to the vascular wall itself. These facts, coupled with the observation that significant atherosclerosis is essentially non-existent in primitive cultures even in individuals of advanced age, justifies the inference that characteristics intrinsic to the vascular wall play a far secondary, if any, role in the pathogenesis and progression of atherosclerosis.
It would then appear that res ipsa loquitur when it comes to environmental and behavioral factors operating through humoral mediators as the predominant cause of atherovascular disease. The same, however, cannot be said for cholesterol as the cause of atherosclerosis and its sequelae. Though extraordinary resources have been devoted to cholesterol by public health agencies and the pharmaceutical industry to the point where this vision rules supreme in the public consciousness almost to the exclusion of any other possibility, the evidence in support of cholesterol is controversial at best.
The dominance of cholesterol as the designated causative factor in atherosclerosis is an unfortunate reality that has not only led to a squandering of resources, but also to a vast array of recognized and unrecognized complications due to only partially effective, or outright ineffective treatment regimes. All of the statins, for example, required serial clinical trials to demonstrate any clinical efficacy; yet, in spite of only tenuous evidence regarding their efficacy and their known significant side effect profile (statins cause overt severe side effects such as hepatitis and myositis, as well as more insidious cognitive loss and erectile problems due to their complex effects on cholesterol metabolism), cholesterol-targeting drugs consistently occupy top positions in the list of most-prescribed (and most profitable) drugs.
Considering the lack of efficacy and poor risk-reward profile of cholesterol-related interventions, it is puzzling why cholesterol should have become so prominent a rallying cry; after all, the oft misquoted Framingham Study, along with numerous subsequent follow-up cohorts such as the Physician's Health Study, the British NHANES and numerous other investigations worldwide have demonstrated clearly that any association between cholesterol and cardiac disease is statistical at best, and less important than hypertension, for instance.
The current “war on cholesterol” rests on pioneering (and deeply flawed) studies by Ancel Keys, PhD, as well as subsequent tissue studies noting the presence of cholesterol in “foam cells” found within the walls of damaged blood vessels. It was then theorized—though never studied or conclusively proven—that these “foam cells” originate from myocyte precursors that somehow decide to begin “sucking out” cholesterol from the bloodstream and thus swell to become “foam cells”. These cells, in turn, are purported to release fatty acid precursors when they die and deteriorate. The released fatty acid then causes more local inflammation, which produces more damaged myocytes susceptible to the influence of cholesterol and thus propagates the initial insult. Periodically these damaged myocytes then “heap-up” and the cap of this “plaque” ruptures, exposing a surface that attracts platelets and causes an intra-vascular “plug”—a “vaso-occlusive crisis”.
In spite of the clear and convincing evidence contradicting this theory, (ÁRSLL JÓNSSON, BJARNI A. AGNARSSON and JÓNAS HALLGRÏMSSON, “CORONARY ATHEROSCLEROSIS AND MYOCARDIAL INFARCTION IN NONAGENARIANS: A RETROSPECTIVE AUTOPSY STUDY, Age and Ageing, Volume 14, Number 2, Pp. 109-112), tens of billions of dollars have been devoted annually worldwide to popularizing and marketing the urban legend of a sudden intra-vascular luminal obstruction arising out of a spontaneous, insidious and inexorable process of lipid deposition. In addition to the aforementioned stranglehold on the pharma best-seller charts, cholesterol also dominates the invasive cardiovascular (and CNS and peripheral vascular) market in terms procedures built around its management. In fact, two prominent medical subspecialties—interventional cardiology and (cardio)vascular surgery—have been built exclusively based the concept of “relieving atherosclerotic obstructions”.
Rather than a scientific basis, the key to the popularity of the cholesterol hypothesis lies in its visual—and visceral—impact. The sophisticated graphics splayed all over the media to sell this concept are particularly effective because of fats' linkage to bile secretion and the ability of out-of-context visual images of fat to induce nausea when not accompanied by the aroma of actual food. The “cholesterol blockage” is drawn in exquisite, greasy detail with nauseating little droplets of fat dripping through it. We are told that opening this “blockage” would somehow relieve an “obstruction”; this resonates with human nature, which is interferential. People want the matter “taken care of” and the most demonstrably interferential the “treatment”, the more satisfying the “cure”. What more satisfying, therefore, then relieving a “blockage”?
Yet cholesterol metabolism disarray as the exclusive causative factor in the genesis of cardiac and vascular disease is untenable. Cholesterol as the main culprit not only runs contrary to common sense in terms of ignoring the presence of a robust barrier—the endothelium—to the initiation of this disease cycle, but it also faces an increasing body of scientific and statistical evidence contradicting it. After decades of exhaustive research, the mechanism whereby cholesterol would initiate and then propagate vascular injury within the blood vessel remains elusive. In fact, the cholesterol/atherosclerosis data cycle has undergone so many iterations that most scientists and practitioners now view with cynicism the arrival of the newest “latest and best” data. Cholesterol drugs (except for niacin, the original and still most effective intervention in this respect) have required so many “studies” and “statistical revisions” to show any effect whatsoever that the original data has effectively disappeared in the process.
Even more damning, the emergence of today's very effective cholesterol reducing drugs has had a paradoxical derogatory effect on the reputation of cholesterol as the arch-villain. Now that statins, as well as modulators specific to just about every subsegment of the cholesterol/triglyceride continuum have become available, precise and strict control of cholesterol levels has become possible in even the most dyslipidemic patient. Yet the predicted dramatic benefits in terms of reduction of morbidity and mortality have failed to materialize and repeated studies attempting to demonstrate regression of plaque upon strict control of cholesterol have proven an utter failure. (Some IVUS—Intravascular Ultrasound—based studies claimed to demonstrate plaque regression on the order of 1 to 2 percent over a period of 24 or so months; these results were claimed to be not only statistically significant, but downright “dramatic”, even though the population cohorts of these studies were small (on the order of 100 to 200 patients) and within the measurement variability for IVUS).
Most problematic of all is the fact that “bad cholesterol” makes zero sense from an ontological perspective. Cholesterol's claim to being the progenitor of atherosclerosis would be immeasurably strengthened if someone came up with even the slightest Darwinistic survival advantage to elevated LDL cholesterol, yet no one has been able to divine such an advantage.
This is in direct contrast to platelets, whose complex and difficult role in homeostasis mandates a direct and dramatic downside in terms of vascular patency. A downside so dramatic, in fact, that even animals seem to be aware of it, as various species have been observed to chew on willow bark in spit of its bitter and unpalatable taste.
It is commonly accepted that willow bark's medicinal properties were originally discovered by primitive cultures by observing this animal behavior. It was initially theorized animals gravitated towards this medicine because willow bark's anti-inflammatory effects. However, there is an alternative possibility: while salicin (the primary anti-inflammatory in willow bark) itself is not considered to have strong anti-platelet properties, willow bark does contain other compounds that do. Could it be that at least in part animals chew on this bark to regulate their clotting and platelet thermostat and that this in some way does confer sufficient Darwinistic survival advantage to promote those individuals that do have this habit? (Some species of animals will also root out onion bulbs in nature, even in the middle of winter. Wild onions are not sweet and there appears to be no other cause than medicinal properties to seek them out).
The possibility exists that many species have platelet counts with pathologic vascular consequences in the long term. These effects are irrelevant in nature, however, because most animals don't live long enough to see these negative consequences (and also because many species simply don't have large enough arteries to experience turbulent flow). Even when it comes to human beings, while homo sapiens developed the genetic capacity for a relatively long life span in prehistoric times, trauma and infection remained by far the most important mechanisms of demise throughout known human history. Life expectancies did not exceed the three decade mark in many societies until the mid 19th century and continues to hover around this figure in several undeveloped nations today (Swaziland, Mozambique, Zambia, Sierra Leone. Source: United Nations, CIA World Factbook, etc.).
It follows from the above that the survival impact of rapid and effective hemostasis in nature far outweighs any possible increases in the incidence of intravascular events caused by high platelet counts. Further, it is logical to assume that if the coagulation cascade and hemostasis apparatus can be demonstrated to be a participant in the development of vascular disease—which they are known to be—then it is irrefutable that the survival traits of rapid hemostasis are in direct conflict with the requirements of long term vascular patency. In other words, there is a “coagulation and hemostasis thermostat”, which thermostat has been set to maximum rapidity and efficacy, at the expense of optimal blood vessel patency.
Which brings us to platelets and the expression “Everything old is new again.” As far back as 1950—far before cholesterol was considered anything but a steroid precursor—Dr. Lawrence L. Craven, MD noticed that aspirin inhibited platelet function and that it also dramatically reduced cardiovascular events. Platelets then instantly shot to the forefront in the selection process of a cause for atherosclerosis. For various reasons, however, platelets fell by the wayside in the competition with cholesterol as the primary candidate for investigation.
The first and foremost reason why the platelet theory of atherosclerosis lost its initial momentum was simple economics: it is exceedingly difficult to derive profit from a commonly available and very inexpensive remedy such as aspirin. Nevertheless, as shall be discussed later, there were also some truly confounding studies that did justifiably challenge platelets' role in atherogenesis. Which doesn't negate the vast body direct and indirect evidence that demonstrates that abandoning this original line of thought was a grave mistake.
While aspirin can admittedly lead to dangerous bleeding, tracing the atherosclerosis back to the platelet itself would have led investigators to consider the option of eliminating even aspirin from the equation. Yet it appears that simple mechanical or pharmacologic reduction of platelet counts (with some caveats, as shall be outlined later—what is really meant here is reduction in total platelet activity, for which platelet counts may serve as a surrogate index under some circumstances) is a treatment option that has never been seriously investigated. Which is surprising, since—unlike as it is the case with aspirin—it is known that platelet counts as low as 50,000 per microliter confer no additional risk of bleeding (as long as the platelets present are normal in morphology and function).
If the medical research industry were indeed unbiased, never mind actually efficient, the least that should have happened at some point was that at least a single researcher should have raised the possibility of reducing platelet counts (with or without aspirin as an adjutant) as a treatment alternative. Logic dictates that even in the absence of the unique observations of the applicant of this patent (confirmed by multiple cardiovascular colleagues) that patients with chronic platelet counts significantly below normal exhibit neither acute, nor chronic endovascular disease, at least one prominent researcher should have sought to mimic the effects of aspirin through a different means, if for no other purpose than to further elucidate the mechanism of its function.
Instead, we now know a lot about aspirin's mode of action without any attempts to enhance its effects or improve its safety profile. There are now copycat drugs available that are less effective and less safe. And, though we know that the primary mode of failure of aspirin is acetylation-resistance, and we also know that a significant proportion of patients are therefore resistant to aspirin's anti-platelet effects, almost nobody in clinical practice gets tested for such resistance.
Similarly, one of the fundamental tenets of basic logic (first stated by Aristotle) is that if the opposite of a statement is untrue, than the statement must be true. Applying this principle to platelets, the corollary to the observation that patients with essential thrombocytopenia do not develop endovascular disease is the undeniable fact that ALL hemodialysis patients (even those with very low cholesterol) inevitably develop horrendous and widespread atherosclerosis after a very short time on this treatment.
While hemodialysis lowers platelet counts, it is because dialysis activates platelets; this also releases platelet-related mediators. Suprisingly, small scale studies indicate that the rates of atherosclerosis and peripheral vascular disease are similar in patients who are dialyzed peritoneally. This observation makes perfect sense, however, once we consider that PD patients also suffer from elevated Blood Urea Nitrogen (BUN) and uric acid rendering their platelet function abnormal, while retaining more platelets to produce direct intravascular injury as compared with HD (hemodialysis) patients.
It is fascinating to note that GOUT is also known to pose a significant (though little discussed) cardiovascular risk. This risk, which is much higher than that posed by even dramatically elevated cholesterol levels, not only ties in with the above observation about PD and HD, but also with the article by Miha Furlan, Ph.D., Rodolfo Robles, Miriam Galbusera, Sc.D., Giuseppe Remuzzi, M.D., Paul A. Kyrle, M.D., Brigitte Brenner, Manuela Krause, M.D., Inge Scharrer, M.D., Volker Aumann, M.D., Uwe Mittler, M.D., Max Solenthaler, M.D., and Bernhard Lämmle, M.D., entitled “Von Willebrand Factor-Cleaving Protease in Thrombotic Thrombocytopenic Purpura and the Hemolytic-Uremic Syndrome” and published in Nov. 26, 1998 in The New England Journal of Medicine, (No. 22, 339:1578-1584) (this issue shall be discussed further in the Prior Art and Detailed Description of the Invention).
As shall be discussed later, this observation that in high uremic states von Willebrand factor may be dysfunctional and that HD and PD patients thus have comparable rates of atherosclerosis not only further strengthens the case for the pathogenicity of platelets, but also emphasizes that platelet count and total body platelet activity are not synonyms and must be separated in any proposed treatment regime (though they can converge temporarily, such as in the steady state of platelet reduction, in which case platelet counts can serve as a surrogate measurement for total body platelet activity).
Indeed, defective processing of von Willebrand polymers due to any cause leads to increased platelet aggregation and activation and thus vascular disease, as will be discussed in the Prior Art. Based on this evidence, reduction of von Willebrand levels is prescribed by U.S. Pat. No. 7,192,914. This concept is based on Valentin Fuster and E. J. Walter Bowie's animal studies entitled “Von Willebrand's disease in pigs and atherosclerosis”, published October 1979 in the International Journal of Clinical & Laboratory Research. The above cited study found that in the pig animal model von Willebrand's disease (i.e.: a deficiency of von Willebrand factor) is protective of atherosclerosis. This conclusion was bolstered by the observation by Frank W. G. Leebeek, MD, PhD, Irene M. van der Meer, MD, PhD and Jacqueline C. M. Witteman, PhD in their article entitled “Genetic Variability of von Willebrand Factor and Atherosclerosis”, published 2004 in Circulation (110:e57) that increased levels of von Willebrand factor are associated with an increased incidence of atherosclerosis. An exact mechanism for this finding has neither been postulated, nor proved, but is not unexpected given that von Willebrand factor not only has a role in coagulation, but also platelet aggregation and activation. Which suggests that this “von Willebrand effect” is secondary to this agent's effects on platelets (and the disease is thus better treated by going straight to the cause).
Proceeding along the chain of evidence of platelet activation, Glanzmann's thrombasthenia is a genetic dysfunction of the IIb/IIa receptor that prevents platelet activation. Glanzmann's would appear to present a perfect real-life laboratory to study platelets as a potential causative factor of atherosclerosis. Since patients with Glanzmann's are known to suffer from impaired activation of their platelets, it would seem that having Glanzmann's is tantamount to having a reduction in platelet counts.
Glanzmann's patients were long believed to be exempt from atherosclerosis. This was based on clinical observations that Glanzmann's patients bleed but do not get heart attacks. O. Shpilberg, MD, MPH, I. Rabi, MD, K. Schiller, R. Walden, MD, D. Harats, MD, K. S. Tyrrell, PhD, B. Coller, MD and U. Seligsohn, MD. contest this assumption in their article entitled “Patients With Glanzmann Thrombasthenia Lacking Platelet Glycoprotein IIbβ3 (GPIIb/IIIa) and vβ3 Receptors Are Not Protected From Atherosclerosis”, published 2002 in Circulation (105:1044-1048).
Unfortunately, the diminutive sample size—seven patients—is a serious flaw of this study. Glanzmann's patients demonstrate great bleeding and atherosclerosis variability (due to genetic heterogenicity) and such a sample size is not likely to be adequate. Also, there was no pathologic study to follow up the findings (ultrasound is an imprecise diagnostic tool with poor spatial resolution). But the fact that renders this study completely irrelevant is the known fact that Glanzmann's platelet are very much active (just not via the IIb/IIIa mechanism).
Mechanical activation of platelets easily explains how Glanzmann's patients can have atherosclerosis yet be free of ACS. For here it must be emphasized that while the prevailing rates of atherosclerosis in Glanzmann's may be controversial, it is still accepted that rates of cardiovascular events are considerably decreased. At first glance Shpilberg would appear to be in the clear, since he's careful to point out that his intent is not to investigate occlusive events, but rather to test the assumption that “platelets have been suggested to play a role in the early development of atherosclerosis”.
Nevertheless, given the fact that mechanical activation is most likely to occur in large caliber vessels (the study measured carotid intima thickness and the carotid is known as a large caliber vessel with turbulent flow leading to mechanical platelet activation), as well as close downstream from embolization sources (the aortic valve and aortic bulb, even more prominent sites of turbulence), this study is shockingly irrelevant in terms of trying to identify Glanzmann's impact on atherosclerosis. Intermediate or low caliber vessels with proven laminar flow should have been used as target sites of this study and thus the only inference to be drawn from the findings is that Glanzmann's does not equate to having no platelets and—once again—that platelet counts and platelet activity are not synonyms.
The review article entitled “Glanzmann's Thrombasthenia”, by Alan T. Nurden, published 2006 in Orphanet Journal of Rare Diseases (1: 10) presumes to sum up the status quo regarding Glanzmann's in the following fashion: “ . . . Since therapeutic inhibition of platelet αIIbβ3 function prevents arterial thrombosis, patients are empirically protected from this disease. It has been speculated that patients with GT may also be protected from atherosclerotic disease. However, studies within ethnic groups in Israel have suggested that this is not so. Patients with GT also are not protected against venous thrombosis, where plasma coagulation factors are of primary importance.” Unfortunately, however, Nurden's conclusions (i.e.: about Glanzmann's providing no protection against atherosclerosis) must be discounted, as the article refers back to the Schpilberg study as its primary proof.
Referring back to the section on hemodialysis, it's easy to understand how mechanical activation renders any biochemical defect completely irrelevant in terms of the atherogenic potential of platelets. And this effect can even extend to the microvasculature—and, thus laminar flow zones—as evidenced by the phenomenon known as “pump head”, experienced by cardiovascular bypass (“perfusion”) and extra-corporeal membrane oxygenation (ECMO) patients. While the cause of this phenomenon is not known for certain, it has been assumed to be due to activated and microaggregated platelet clusters. It is logical to conclude that the process of hemodialysis activates platelets in a manner similar to the cardiovascular bypass machines—to the extent that most patients need to be heparinized during dialysis just to avoid whole body thrombosis—and that this is the reason why patients on hemodialysis have tremendously accelerated progression of atherosclerosis.
Progressing beyond clinical observations to more rigorous scientific data, hematologic studies have revealed that platelets are the most unstable of all cells in the body. Anatomic and post-mortem studies have noted that the earliest and most severe forms of atherosclerosis in the body occur at sites of maximum turbulence, such as in the aorta at the impact of a jet from a stenotic aortic valve. This mechanism of injury could only be due to intimal susceptibility or some unrecognized platelet effect, as platelets are the only component of blood activated in such turbulent jets. However, if atherosclerosis was really a result of intimal susceptibility (rather than inability to resist platelet erosion forever), then there should be at least a few early lesions in small vessels, on a random basis. Which is not the case.
There's even bench scientific research data to explain some of the mechanisms whereby platelets might in fact be the mediators of even cholesterol-related damage. As a for instance are supplied three references addressing the correlation of megakaryocyte dysfunction in diseases states (specifically, diabetes), the effect of fat ingestion on platelet function and the platelet size (as a marker of platelet activation) as a positive risk for acute myocardial events (i.e.: as a marker of acute endovascular injury), respectively.
More remarkably, scientists are also succeeding in elucidating the detailed mechanisms of modulation that regulate platelets' long term effects on the vascular endothelium. Several factors have been isolated which potentiate platelets' negative effects on the endothelium and the vascular wall. It is known that Angiotensin II in the circulation leads to the upregulation of NF Kappa B (Nuclear Factor Kappa B) and subsequent VCAM (Vascular Cell Adhesion Molecule 1) and PAI-1 (Plasminogen Activation Inhibitor 1) production, both of which enhance the progression of atherosclerosis and even gross vascular deformities such as aneurysms. Similarly, the presence and induction of activated Protein C (APC) complexes also accelerate the progression of atherosclerosis. Genetically manipulated mice with increased PAI-1 expression are reported to show more rapid spontaneous stepwise progression of atherosclerosis, though this is controversial. PAI-1 is a factor that modulates the coagulation cascade and is released from activated platelets.
Endothelin is another factor that modulates platelet function and exhibits a role in the genesis of atherosclerosis. Endothelin inhibits platelet aggregation, but has surprisingly been reported to be elevated in patients with atherosclerosis in an article by C. Thiemermann, G. R. May, C. P. Page, and J. R. Vane entitled “Endothelin-1 inhibits platelet aggregation in vivo: a study with 111indium-labelled platelets, published February 1990 in the British Journal of Pharmacology (99(2): 303-308). On face value, this would suggest that a compound that somehow contributes to the genesis of atherosclerosis does so in spite of the fact that it inhibits platelet activity; unless, of course, endothelin is a reaction to endovascular pathology and an attempt by the body to stem the damage from platelets by inhibiting their aggregation.
There is also proof that platelets are responsible for the progression of endovascular disease. As one would expect based on the fact that a scar is a late response to an injury to which the initial response is platelet activation and a platelet plug, platelets have been conclusively demonstrated to be the primary stimulus for fibroblast growth. Platelet extracts cause visible increase in fibroblast activity; this effect is sufficiently dramatic that it can demonstrated through gross cell culture assays and can be visually observed and quantified. And fibroblasts have been noted to uptake lipids and to integrate surrounding debris into the collagenous matrix they secrete to form the predominant bulk of the scar itself. This makes fibrocytes a much better candidate for the role of agents of vascular decay then the “degenerate” myocytes purported to be the responsible for this phenomenon, since myocytes are not known to uptake lipids in any other area of the body (i.e.: skeletal or smooth muscle cells).
Platelets (and compounds released by platelets) have a similar inflammatory effect on white cells and multiple other blood and vascular components. This fact will explain why an association—but not causal!—has been found between ACS and inflammatory indices such (CRP and ESR).
The central role of platelet function is thus demonstrated by clinical observations, clinical studies and hard science data. What's more, some of this hard science data has been extended into the clinical (or, in this case, post-clinical) realm. Specifically, the above mentioned fibrosing and inflammatory effects have been mapped to the plaques that first arise and are usually most severe at areas of maximum turbulence, such as artery bifurcations, sites of jet impact or in the lumen and near bends or tortuosity of large vessels. In this regard, it should be noted that many elderly patients will have as their only sites of atherosclerosis the aorta distal to a stenotic aortic valve, and/or the carotid distal to the carotid bifurcation. For a detailed discussion, the reader is referred in this matter to the tome Vascular Surgery, by Robert W. Hobson, Samuel E. Wilson and Frank J. Veith, pages 42-48.
It should be noted that at first read even the cited reference appears to contradict the above assertions, namely that the location of plaques proves they're caused by platelets. Specifically, the authors go to great lengths to defend the cholesterol hypothesis by quoting studies claiming plaque regression in monkeys on low cholesterol diets. The authors seek to “debunk” the theory that activation of platelets may be involved in atherosclerotic plaque genesis by claiming that maximum plaque deposition occurs in areas downstream from areas of maximal turbulence, rather than areas of maximum turbulence, per se. Which makes perfect sense once more, as mechanical platelet activation is not instant, and these plaques occur just far enough downstream from the original jet that triggers platelet activation to account for the time delay in activation.
Faulty reasoning has become doctrine because even proponents of the platelet hypothesis have failed to adequately study the science behind these phenomena, though the evidence does exist to deduce the pathophysiology. For instance, we know from studies of hydrodynamics that the Reynolds number determines the nature of flow; we also know from real life studies that transition from laminar to turbulent flow is a hysteresis type of transition within a range from 1900 to 2300. Turbulent streams thus inevitably form a cone with a shifting tail that retains turbulent characteristics for a considerable distance downstream into the laminar zone, tapering from the lower velocity flow at sides of the vessel towards the higher velocity center (where the Reynolds number thus remains higher). And, as mentioned above, we know from studies of platelet function that platelet activation is not instantaneous, but rather occurs on the scale of microseconds, which explains the millimeter to centimeter downstream displacement of atherosclerotic plaques from the point of maximum turbulence (BUT STILL WITHIN AN AREA OF TURBULENCE!!!). This rule is further supported by an exception, namely the inevitable aforementioned post-stenotic aortic plaques associated with aortic valve stenosis. Engineering analysis of the jet from such a valve will show Reynolds numbers an order of magnitude greater than those of local turbulence in secondary vessels. It is the markedly increased kinetic energy of this stream that explains why there is no downstream displacement of this aortic plaque; this increased velocity and kinetic energy of the jet causes the platelets to impact against the vessel wall with such speed that they are mechanically damaged and forced to discharge their contents, rather than be activated by the standard route.
One would think that such a compelling chain of evidence would at least mandate some clinical investigation. Unfortunately, however, the current patent is the first to recognize the above explanation for the physical distribution of atherosclerotic plaques in the human body. Further, the current application (and its precursor) is the first to point to the Glagov phenomenon (asymmetric eccentric centrifugal hypertrophy prior to concentric centripetal intrusion of plaque into the lumen) as further proof of this explanation (see original submission), as the eccentricity of atherosclerotic plaques proves that they are a flow-related phenomenon (in contrast to the metabolic hypothesis, which claims that cholesterol is the causative agent of atherosclerotic plaques, but which—if true—would have to produce symmetric circumferential plaques, since cholesterol is evenly distributed in the blood stream and cholesterol is neither activated, nor mal-distributed by turbulence).
So it is a shameful state of affairs that, aside from the consensus that Aspirin is dramatically effective in the reducing the incidence and severity of cardiovascular events, there appears to be complete apathy regarding the long term role of platelets in the pathogenesis of atherosclerosis. And even when it comes to acute “vaso-occlusive events”, there is only one large scale study (Philip Bath, MD, FRCP, Charles Algert, MPH, Neil Chapman, MRCP and Bruce Neal, MRCP (UK), PhD for the PROGRESS Collaborative Group, Association of Mean Platelet Volume With Risk of Stroke Among 3134 Individuals With History of Cerebrovascular Disease. Stroke. 2004; 35:622-626) that sought to examine the role of platelets in the pathogenesis of such events. The study generated little excitement, as it concluded that elevated PLATELET COUNTS from did not cause an excess of strokes over people with normal levels. However, what was found was that elevated aggregate PLATELET VOLUME—i.e.: the estimated total platelet volume within a body—did correlate with the various endpoints for such events analyzed by the study. Which brings us back once more to the caution: platelet counts and platelet activity are not synonyms.
But are platelet volume and platelet activity synonyms? And, if they are, why would they be? Authorities such as Bernd van der Loo, MD and, FRCP, FESC John F. Martin, MD, who in their “Megakaryocytes and platelets in vascular disease” (Bailliere's Clinical Haematology: Megakaryocytes and Platelet disorders, February 1997, Pages 109-123) explain that individual platelet volume is correlated with platelet activation status, since platelets are known to swell once they activate. It thus makes sense that an increased aggregate volume even in the face of normal platelet counts would lead to an increased number of intra-vascular events, as opposed to rote platelet counts which can represent platelet masses of highly variable activity.
Incredibly, there has never been a study conducted into the DECREASE in the incidence of atherosclerosis and intra-vascular events in patients with ESSENTIAL THROMBOCYTOPENIA, or other conditions that would artificially reduce platelet counts without platelet activation (ITP and some forms of HIT; TTP and HELLP activate platelets and cause thrombocytopenia by way of consumption). The lynchpin for this application thus remains the suprising personal and polled peer data regarding the absence of angina, myocardial ischemia and myocardial infarct among patients with essential thrombocytopenia—data not available to anyone else prior to submission of this patent application.
Which brings us to keystone of the argument that platelets cause atherosclerosis (and a whole lot else): the efficacy of aspirin. In this day and age of nanotechnology, heroic medical interventions and two dollar a pill cholesterol marvels, the single most effective intervention in the prevention and treatment of vascular disease remains Acetyl salicylic acid (Aspirin).
Particularly for “vaso-occlusive disease”, low doses of aspirin with low incidences of complications (less than 1% incidence of major haemorrhage) result in morbidity and mortality reductions of 45% (Physician's Health Study). This is even more remarkable in the light of the fact that we now know that up to 50% of patients treated with aspirin are “non-responders”, meaning genetically resistant or immune to its acetylating effects. Essentially, what this means is that almost all patients who are susceptible to the effects of Aspirin will see a dramatic effect in terms of endovascular morbidity and mortality.
Granted, the above cited study was conducted at a time when most physicians were males and the study population was thus essentially all male. Recent attempts to study exclusive female cohorts have failed to show a similar cardiovascular benefit, though they have demonstrated a clear CVA-reduction effect. Nevertheless, aspirin's effects in males and in symptomatic cardiovascular patients of both sexes have been confirmed repeatedly. Which means that, while atherosclerosis will probably prove to be multifactorial in origin, there is already overwhelming evidence that platelets occupy the central role.
Unlike the crackpot theories the cholesterol industry periodically parades and then debunks, such as chelation therapy, high dose vitamin C, beta-carotene, meditation and hypnosis, properly designed platelet directed interventions stand a very good chance of conquering this very serious disease. Poor dental hygiene and caries might very well have a role, as might the favorite all-purpose villain of twentieth century medicine, “inflammation”, and its corollary, “auto-immune disease”, but breakdown of the arterial wall cannot occur in the absence of platelet-related damage (except in conditions of inherent vascular wall abnormality, such as Marfan's syndrom and Ehlers-Danlos). Yet more money has been spent by the ADA (American Dental Association) trying to prove that atherosclerosis is related to poor oral hygiene, then by the AHA (American Heart Association) just reiterating the fact that there is clear and incontrovertible proof that atherosclerosis is a direct result of platelet-mediated damage to blood vessel walls.
Which brings us to the logical and simplest solution to what shall indubitably prove to be an exceedingly complex disease: eliminate the culprit. Reduce the number of provoking entities, namely the number of ACTIVATED platelets, available to injure. What's more, benefits of this treatment will likely extend to a number of other pathologies, since atherosclerosis is already proving to be only a small part of a vast continuum of platelet-related damage. There is now evidence to suggest that many conditions previously considered to have no connection to vascular pathology may in fact be a direct result of it. As a for instance, we know now that effect of platelets is not confined to the endovascular lumen. The initial establishment of tumors is not possible without angiogenesis. Thrombin receptors have been proven to have a role in this initial angiogenesis. Platelets have a role in modulation of thrombin receptors. Reduction of platelet activity (and reduction of vascular pathology, such as atherosclerosis) to safe levels might affect thrombin receptor levels.
Similarly, MS—Multiple Sclerosis, formerly a mainstay of the “autoimmune” mania, now also has a proposed vascular mechanism. Alzheimer's mysterious “fibrillary tangles” are also intriguing and would make a whole lot more sense from a vascular/platelet perspective. The list of potential platelet-mediated phenomena is endless, which is why it is so imperative to establish the current evidence and thus provide the foundation for the research necessary to fully explore its implications.
While many of the fundamentals of this treatment are supported by solid evidence, much work does remain. Patients with functional platelet counts down to 50,000 per microliter (i.e.: patients who are not uremic, in DIC, or have no other specific platelet dysfunction) are considered to have no excess bleeding risk based on clinical experience, but there hasn't been a single study to date to examine whether such a reduction is indeed completely safe. Thus, this may prove to be an erroneous assumption once more rigorous investigations are completed. Also, current methods to reduce platelet counts may prove inadequate to the task of reducing the incidence of and treating atherosclerosis and atherosclerosis-related pathology.
But whatever the technical difficulties and however much information is lacking in this area, one thing will be proven beyond a shadow of a doubt through the course of this discussion: platelets are the primary culprit of endovascular disease and their sequelae. While all treatment to date has focused on indirectly modulating their effects, the only foolproof method of ameliorating the harm from unnecessarily high platelet activity is to contain the culprit. Hence, this patent.